From Cancer Villain to B-Cell Hero

In each cell of the body is a busy factory, containing all of the elements needed for that cell to develop and perform its unique function. A neuron sprouts a long extension and develops the ability to conduct electrical impulses. A liver cell secretes bile and can absorb toxic substances to neutralize them. Muscle cells elongate, form multiple nuclei and build long fibers that contract powerfully when stimulated.

But as different as the end product may be, the machines that make up the inner workings of these cells are largely the same, built from the identical set of genetic instructions that all cells share. Indeed, all of the body’s hundreds of cell types originate from one ambitious type of cell with the potential to become almost anything – the pluripotent stem cell to which so much scientific attention has been recently paid. What destiny that neutral cell follows is largely determined by how it organizes its factory, placing its machines in various orders that can have dramatically different outcomes.

Charting those interactions in specialized cells is a frequent goal of scientific research, as understanding a cell’s inner workings will help doctors make repairs when something goes wrong. The laboratory of Dr. Marcus Clark, chief of the Section of Rheumatology at the University of Chicago Medical Center, has devoted itself to the machinery of the B cell, the immune system cells responsible for producing antibodies that fight off disease. In a paper published this week in the journal Nature Immunology, Clark’s group fills in much of the story of what signals are involved in a crucial step of early B cell development, and shows that one of those signals, called Ras and typically associated with cancer in other cells, is surprisingly a key component in the healthy formation of a B cell.

“Ras is one of the best described oncogenes out there, it contributes to cancer in a variety of different formats.” Clark said. “It’s always seen as this pro-proliferative thing: if you put Ras in, the cells start dividing autonomously, and that’s cancer. In our hands, Ras turned off proliferation, it was very unexpected.”

B cells are produced in a person’s bone marrow throughout their life, in a process that has several stages. At first, the progenitors of B cells proliferate, building up a large supply of cells eligible for development into the mature form. The signal that determines whether an early B-cell can “graduate” to future development is the presence of a particular receptor called, appropriately enough, the pre-B-cell receptor (pre-BCR).

“Your diploma is your pre-B-cell receptor; if you get your diploma, it means you can go on,” Clark said. “That’s your quality control.”

Through a series of experiments where bone marrow cells from a variety of genetically-modified mice were grown in a dish, Clark and his colleagues were able to determine what processes the pre-BCR sets in motion to push a cell towards development into a full B-cell. If you think of the pre-BCR as a light switch, turning it on initiates a chain of signals – sort of an intracellular Rube Goldberg machine – that culminates in the activation of genes that stop cell proliferation and spur development. To make matters more complex, another receptor called IL7R controls a Rube Goldberg chain with the opposite purpose: keeping those same genes turned off.

Clark’s lab identified the intermediaries in both chains, producing a map of how these two systems are delicately intertwined. Many of those players, including kinases and transcription factors, play similar roles in other cell types. But Ras, a signaling intermediate usually thought of as a cancer-causing bad guy, here plays a crucial role, mediating the two functions that allow B-cell development to progress. Whereas normally Ras activity promotes cell division that can become the uncontrollable proliferation that underlies cancer, at one specific time in the developing B-cell it has the exact opposite effect, putting the brakes on proliferation and, perhaps, preventing the development of leukemia or lymphoma.

“Ras activation normally can cause cancer, and people think of it as a bad player,” Clark said. “But here it’s absolutely necessary for turning off the cell cycle and causing differentiation, enabling the processes you need to make a good B cell.”

So it’s a cellular-level story of redemption – in the right time and the right place, a notorious villain plays the hero. And it’s also yet another demonstration of how biology uses relative simplicity to generate amazing complexity, reshuffling the deck of cellular signals to produce myriad different cell types with vastly different functions.